Biologic Activity of Transferred HIV-specific CD8 Clones

描述（由申请人提供）：目前用于HIV-1感染的抗逆转录病毒治疗（ART）方案可以阻断病毒复制并提供实质性临床获益，但长期治疗可能与显著毒性相关，并且似乎无法根除病毒。增强感染个体免疫系统的策略可能提供一种改善ART对残余病毒复制的控制的手段，并最终使减少对ART的需求成为可能。如果可以定义实现所需抗病毒活性所需的应答的性质和幅度，则将促进有效的基于免疫的疗法的开发。我们的团队在分离、体外扩增和过继转移人病毒特异性CD 8 + T细胞克隆作为建立强大的功能性CD 8 + T细胞应答的策略方面拥有丰富的经验，并对CD 8 + T细胞进行修饰以引入增强T细胞功能的基因，以及使用高度敏感的分子技术来检测PBMC中的病毒库和持续的HIV复制，我们的初步研究表明，通过输注HIV特异性CD 8 + T细胞克隆，随后进行低剂量IL 2的简短疗程，可以在接受低病毒负荷的有效ART的HIV感染个体中实现对HIV的非常高和持续的CD 8+应答。因此，我们建议，以确定是否提供这样的患者与高频率的功能分化的CD 8+效应细胞，特异性的无论是gag或调节病毒蛋白在病毒生命周期的早期表达，可以有助于遏制正在进行的病毒复制和减少持续的病毒水库。此外，与其他慢性病毒感染相比，HIV感染的一个标志是HIV特异性CD 28 + CD 8 + T细胞的下降和CD 28 + CD 8 + T细胞的积累。CD 28共刺激分子表达的丧失，可能来自抗原驱动的分化，对CD 8 + T细胞功能具有显著影响，使细胞越来越依赖于CD 4 + T细胞的帮助。我们的初步研究表明，CD 28可以在CD 28 + CD 8 + T细胞中重新表达，并且这些细胞重新获得产生IL 2的能力，并在特异性靶点识别后增殖。因此，我们建议对HIV特异性CD 28 + CD 8+效应细胞进行遗传修饰，并确定转移的CD 28 + CD 8 + T细胞是否在可检测到血浆病毒血症的个体中表现出改善的存活率、功能和抗病毒活性。

DESCRIPTION (provided by applicant): Current antiretroviral therapy (ART) regimens for HIV-1 infection can block viral replication and provide substantial clinical benefit, but long-term therapy can be associated with significant toxicities and does not appear capable of eradicating the virus. Strategies to boost the immune system of infected individuals might provide a means to improve control of residual viral replication on ART, and eventually make it possible to reduce the requirement for ART. Development of effective immune-based therapies would be facilitated if the nature and magnitude of responses required to achieve the desired antiviral[ activity could be defined. Our group has extensive experience with the isolation, in vitro expansion, and adoptive transfer of human virus-specific CD8+ T cell clones as a strategy for establishing strong, functional CD8+ T cell responses, and with modification of CD8+ T cells to introduce genes that enhance T cell function, as well as with highly sensitive molecular techniques to detect viral reservoirs and persistent HIV replication in PBMC, lymphoid tissue, and mucosal tissue of HIV-infected individuals on potent ART. Our preliminary studies suggest that very high and sustained CD8+ responses to HIV might be achievable in HIV-infected individuals on potent ART with low viral burdens by infusion of HIV-specific CD8+ T cell clones followed by a brief course of low dose IL2. Thus, we propose to determine if providing such patients with a high frequency of functional differentiated CD8+ effector cells, specific for either gag or regulatory viral proteins expressed early in the viral life cycle, can contribute to containment of ongoing viral replication and reduction in persistent viral reservoirs. Additionally, one hallmark of HIV infection in comparison to other chronic viral infections is the decline of HIV-specific CD28+CD8+ T cells and accumulation of CD28+CD8+ T cells. The loss of expression of the CD28 costimulatory molecule, presumably from antigen-driven differentiation, has significant consequences on CD8+ T cell function, rendering the cells increasingly dependent on CD4+ T cell help. Our preliminary studies demonstrate that CD28 can be re-expressed in CD28+CD8+ T cells, and that such cells reacquire the ability to produce IL2 and proliferate following specific target recognition. Thus, we propose to genetically modify HIV-specific CD28+CD8+ effector cells and determine if transferred CD28+CD8+ T cells exhibit improved survival, function, and antiviral activity in individuals with detectable plasma viremia.